Bone metastases are common in advanced cancers including prostate adenocarcinoma, where there is evidence of bone metastases in more than 70% of patients with advanced disease. Despite their prevalence and the important clinical implications, there is currently no widely accepted quantitative imaging assessment for response to therapy. Assessment of response or progression is typically made based on visual interpretation of bone scintigraphy in conjunction with CT and serum markers. The goal of this project is thus to develop, validate, and advance to clinical practice multi-modality quantitative metrics for assessing response of bone metastases to therapy. Combined SPECT-CT systems and the implementation of robust compensation methods has enabled the development of quantitative SPECT imaging methods, which have recently become clinically available. Here we propose to exploit the nexus of these developments via the following 3 aims. (1) Using simulation and phantom studies, we will first optimize and evaluate methods for quantitative SPECT/CT (QSPECT) imaging of Tc-99m MDP. We propose to expand the phantom studies to a QIN cooperative project in order to evaluate the methods across different scanners and centers. (2) Based on these QSPECT methods, we will develop, optimize, and characterize quantitative bone SPECT indices for assessing response to therapy. Computing these indices will involve semi-automatic segmentation of bone and bone lesions, implemented in an integrated software tool. The indices calculated will include the number of lesions, bone lesion burden, and change in lesion uptake with therapy. We will characterize the variability of the indices using realistic simulations and in pre-therapy test-retest studies. (3) Finally, we will apply the methods and validate them in current clinical trials of new therapeutic regimens for bone metastatic castrate-resistant prostate cancer. In these studies, we will evaluate the methods in terms of time to progression and will compare the methods in vivo to similar quantitative metrics estimated from Na18F PET/CT. We will also investigate the amount of additional information provided by whole-body MRI and PSMA PET/CT. We will make the methods and images available to the QIN and propose to organize challenges of segmentation and response metrics to take advantage of the QIN-wide interest in these areas. Together, these quantitative imaging tools and studies will provide a validated approach for quantitative imaging-based evaluation of response in bone metastases that is readily clinically implementable with only a minor increase in cost relative to clinical standard bone scintigraphy.